The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.

Background Among pediatricians, perceived knowledge of efficacy, tolerability, dosing and side effects of antidepressants represent significant sources of variability in the use of these medications in youth with depressive and anxiety disorders. Importantly, the qualitative factors that relate to varying levels of comfort with antidepressants and willingness to prescribe are poorly understood. Methods Using a mixed-methods approach, in-depth interviews were conducted with community-based and academic medical center-based pediatricians (N=14). Interviews were audio-recorded and iteratively coded; themes were then generated using inductive thematic analysis. The relationship between demographic factors, knowledge of antidepressants, dosing and side effects, as well as prescribing likelihood scores for depressive disorders, anxiety disorders or co-morbid anxiety and depressive disorders, were evaluated using mixed models. Results Pediatricians reported antidepressants to be effective and well-tolerated. However, the likelihood of individual physicians initiating an antidepressant was significantly lower for anxiety disorders relative to depressive disorders with similar functional impairment. Pediatricians considered symptom severity/functional impairment, age and the availability of psychotherapy as they considered prescribing antidepressants to individual patients. Antidepressant choice was related to the physician’s perceived knowledge and comfort with a particular antidepressant, financial factors and the disorder-specific evidence base for that particular medication and consultation with mental health practitioners. Pediatricians noted similar efficacy and tolerability profiles for antidepressants in youth with depressive disorders and anxiety disorders, but tended to utilize “therapy first” approaches for anxiety disorders relative to depressive disorders. Parental and family factors that influenced prescribing of antidepressants by pediatricians included parental ambivalence, family-related dysfunction and impairment secondary to the child’s psychopathology as well as the child’s psychosocial milieu. Conclusions Pediatricians consider patient- and family-specific challenges when choosing prescribing antidepressant medications and are, in general, less likely to prescribe antidepressants for youth with anxiety disorders compared to youth with depressive disorders. The lower likelihood of prescribing antidepressants for anxious youth is not related to perception of the efficacy or tolerability, but rather to a perception that anxiety disorders are less impairing and more appropriately managed with psychotherapy.

Background Despite the prevalence of antidepressant-related sexual side effects, comparisons of treatments for these problematic side effects are lacking. Methods To address this, we performed a systematic review and Bayesian network meta-analysis to compare interventions for antidepressant-induced sexual dysfunction in adults. Using PubMed and clinicaltrials.gov, we identified published and unpublished prospective treatment trials from 1985 to September 2020 (primary outcome: the Arizona sexual experience scale [ASEX] score). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Results We identified 57 citations (27 randomized controlled trials, 66 treatment arms, 27 open-label trials, and 3 crossover trials) that evaluated 33 interventions (3108 patients). In the systematic review, 44% (25/57) of trials reported successful interventions; this was more common in open-label (70%, 19/27) compared to placebo-controlled studies (22%, 6/27). In the meta-analysis of placebo-controlled studies that used the ASEX (N = 8), pycnogenol was superior to placebo (standardized mean difference: −1.8, 95% credible interval [CrI]: [−3.7 to 0.0]) and there was evidence that, at a 6% threshold, sildenafil improved sexual dysfunction (standardized mean difference: −1.2, 95% CrI [−2.5 to 0.1]). In the meta-analysis including single-arm studies (15 studies), treatment response was more common with sildenafil, tianeptine, maca, tiagabine, and mirtazapine compared to placebo, but these differences failed to reach statistical significance. Conclusions While heterogeneity across randomized controlled trials complicates identifying the single best intervention, multiple trials suggest that sildenafil ameliorates antidepressant-induced sexual dysfunction. More randomized controlled trials are needed to examine the putative efficacy of other interventions.

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